Regulation of Stalled Replication Forks by ATR
Couch, Frank Benjamin IV
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2014-04-17
Abstract
Errors during DNA replication lead to mutations which contribute to cancer development. To deal with these challenges, cells contain an innate machinery known as the replication stress response. ATR is the master regulator of the replication stress response, and much is known about ATR signaling. However, it is unclear how ATR signaling promotes replication fork repair and prevents pathogenic replication fork processing. In this dissertation, I conducted several studies of the replication stress response to stalled forks. I characterized the protein recruitment and post-translational modifications that occur at replication forks in response to damage using the iPOND methodology. I demonstrated that ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Finally, I began an investigation into the biochemical mechanism by which SMARCAL1 and the related annealing helicases, ZRANB3, UvsW, and RecG, perform fork regression.